Investigational New Drugs

, Volume 36, Issue 2, pp 230–239 | Cite as

First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile

  • Giovanna Speranza
  • Larry Anderson
  • Alice P. Chen
  • Khanh Do
  • Michelle Eugeni
  • Marcie Weil
  • Larry Rubinstein
  • Eva Majerova
  • Jerry Collins
  • Yvonne Horneffer
  • Lamin Juwara
  • Jennifer Zlott
  • Rachel Bishop
  • Barbara A. Conley
  • Howard Streicher
  • Joseph Tomaszewski
  • James H. Doroshow
  • Shivaani Kummar


Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities.


Hsp90 Epichaperome PU-H71 Pharmacokinetics Cancer 



This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contracts No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors thank Dr. Mariam Konaté, Kelly Services, for editorial support in the preparation of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


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Copyright information

© US Government (outside the USA) 2017

Authors and Affiliations

  • Giovanna Speranza
    • 1
  • Larry Anderson
    • 1
  • Alice P. Chen
    • 1
  • Khanh Do
    • 1
  • Michelle Eugeni
    • 1
  • Marcie Weil
    • 1
  • Larry Rubinstein
    • 1
  • Eva Majerova
    • 2
  • Jerry Collins
    • 1
  • Yvonne Horneffer
    • 1
  • Lamin Juwara
    • 2
  • Jennifer Zlott
    • 1
  • Rachel Bishop
    • 3
  • Barbara A. Conley
    • 1
  • Howard Streicher
    • 1
  • Joseph Tomaszewski
    • 1
  • James H. Doroshow
    • 1
  • Shivaani Kummar
    • 1
    • 4
  1. 1.Division of Cancer Treatment and Diagnosis, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Leidos Biomedical Research, Inc.Frederick National Laboratory for Cancer ResearchFrederickUSA
  3. 3.National Eye InstituteNational Institutes of HealthBethesdaUSA
  4. 4.Stanford University School of MedicinePalo AltoUSA

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